The human polyomaviruses are increasingly important opportunistic pathogens among the growing population of immune compromised patients, including those with solid organ transplants and patients receiving immune suppressive treatments for cancer, autoimmune and neurologic diseases. The lack of an animal model of polyomavirus disease has limited our ability to study the mechanisms of immunologic control of polyomaviruses and to develop preventative and therapeutic strategies that could reduce the long-term sequelae of polyomavirus diseases. This 36-month project will build on the established partnership of the Principal Investigator and the NIH-funded Squirrel Monkey Breeding and Research Resource (SMBRR) to: 1) characterize the reactivation of the squirrel monkey polyomavirus (SMPyV) under conditions of immune suppression that predispose to human polyomavirus disease; 2) explore the ability of human polyomaviruses to infect and cause disease in squirrel monkeys; and, 3) test the ability of available antiviral agents to ameliorate polyomavirus reactivation. The proposed studies will broaden the scope of research at the SMBRR to include molecular virologic and immunologic techniques relevant to the health of squirrel monkeys used for biomedical research. In addition, these studies will deliver a model system that can be utilized by other researchers to study the pathogenesis of polyomavirus diseases.